Lyme disease is a major source of morbidity due to the high incidence of rheumatic, cardiovascular and neurologic complications that follow infection with the etiologic agent, Borrelia burgdorferi. In the U.S., close to 10,000 cases are reported annually and it was recently named a "High Priority Research Topic" by the NIAID. Among humans infected but not treated with antibiotics, 80% develop complications but 20% remain disease-free after resolution of a self-limited skin rash. An undetermined number of patients never develop any overt sign of infection and, despite adequate antibiotic therapy, a significant subpopulation still develops debilitating complications. Although described almost twenty years ago, the pathogenesis as well as the immunologic and genetic basis for differing host responses to Lyme disease are poorly understood. Experimental infection of lymphocyte-deficient mice indicates that the innate immune system has sufficient capacity to mediate the most extreme pathologic outcome in this model. Infection of immunocompetent inbred strains of mice recapitulates the spectrum of responses seen in humans. The genetic model of Lyme arthritis using inbred mice is a powerful system to delineate the mechanisms by which adaptive immunity can regulate innate immunity and pathology. Our preliminary evidence indicates that a major immunologic difference between susceptible and resistant hosts is the magnitude of pro-inflammatory response directed by T helper type I cells. Pathology-prone hosts also uniquely exhibit increased activation of NK cells following infection as well as an MHC association with the H-2k haplotype. This proposal seeks to define the immunoregulatory requirements, host polymorphisms and genetic control that lead to differing phenotypic outcomes in experimental Lyme arthritis. Specific aims encompass the following areas: Cytokine gene expression in the lymphoid organs and sites of pathology of infected mice, in vitro analysis of inter-strain differences in cellular immunoresponse, infection of immunologically perturbed mice with reconstitution of immune cell populations, and genetic analysis of select inter-strain crosses of susceptible and resistant mice. Because this model deals with the microbiologic control of a foreign pathogen, the pathogenesis of inflammation and differential host response to a fixed stimulus, the proposed studies should provide broad insight into microbial pathogenesis, inflammatory conditions of multiple organ systems and the genetic basis for susceptibility to infectious and rheumatic diseases.